TNFalpha up-regulates SLUG via the NF-kappaB/HIF1alpha axis, which imparts breast cancer cells with a stem cell-like phenotype

• Published in: Journal of cellular physiology Vol. 225; no. 3; pp. 682 - 691
• Main Authors: Storci, Gianluca, Sansone, Pasquale, Mari, Sara, D'Uva, Gabriele, Tavolari, Simona, Guarnieri, Tiziana, Taffurelli, Mario, Ceccarelli, Claudio, Santini, Donatella, Chieco, Pasquale, Marcu, Kenneth B., Bonafè, Massimiliano
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.12.2010
• Subjects: Breast Neoplasms - genetics; Breast Neoplasms - immunology; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Calcium-Binding Proteins - metabolism; Cell Line, Tumor; Estrogen Receptor alpha - metabolism; Extracellular Matrix - metabolism; Female; Humans; Hyaluronan Receptors - metabolism; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Inflammation Mediators - metabolism; Intercellular Signaling Peptides and Proteins - metabolism; Jagged-1 Protein; Membrane Proteins - metabolism; Neoplasm Invasiveness; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - immunology; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; NF-kappa B - genetics; NF-kappa B - metabolism; Phenotype; Recombinant Proteins - metabolism; RNA Interference; Serrate-Jagged Proteins; Signal Transduction; Snail Family Transcription Factors; Spheroids, Cellular; Transcription Factors - genetics; Transcription Factors - metabolism; Transfection; Tumor Necrosis Factor-alpha - metabolism; Tumor Suppressor Protein p53 - metabolism; Up-Regulation
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.22264

Extracellular and intracellular mediators of inflammation, such as tumor necrosis factor alpha (TNFα) and NF‐kappaB (NF‐κB), play major roles in breast cancer pathogenesis, progression and relapse. SLUG, a mediator of the epithelial–mesenchymal transition process, is over‐expressed in CD44+/CD24− tumor initiating breast cancer cells and in basal‐like carcinoma, a subtype of aggressive breast cancer endowed with a stem cell‐like gene expression profile. Cancer stem cells also over‐express members of the pro‐inflammatory NF‐κB network, but their functional relationship with SLUG expression in breast cancer cells remains unclear. Here, we show that TNFα treatment of human breast cancer cells up‐regulates SLUG with a dependency on canonical NF‐κB/HIF1α signaling, which is strongly enhanced by p53 inactivation. Moreover, SLUG up‐regulation engenders breast cancer cells with stem cell‐like properties including enhanced expression of CD44 and Jagged‐1 in conjunction with estrogen receptor alpha down‐regulation, growth as mammospheres, and extracellular matrix invasiveness. Our results reveal a molecular mechanism whereby TNFα, a major pro‐inflammatory cytokine, imparts breast cancer cells with stem cell‐like features, which are connected to increased tumor aggressiveness. J. Cell. Physiol. 225: 682–691, 2010. © 2010 Wiley‐Liss, Inc.